Monday, July 05, 2010

The Society of Hospital Medicine urges the FDA not to approve generic Lovenox

Why??? I'm not sure I understand why, but SHM apparently does receive considerable support from Sanofi-Aventis, the maker of Lovenox.

In typical fashion, Roy Poses at Health Care Renewal is all over this. He quotes this from a recent WSJ article (my italics):

WASHINGTON—A medical researcher and two medical groups with financial ties to Sanofi-Aventis SA have asked federal regulators to hold off on approving generic forms of a Sanofi blood-thinner, the latest twist in a long running battle to market generic versions of a drug with annual sales topping $4 billion.

Citing potential patient safety issues, the head of the Society of Hospital Medicine and a medical researcher at Duke University last month sent letters to the Food and Drug Administration contending that Lovenox is too complex for any generic maker to copy fully.

Too complex to copy fully? I'm no expert in pharmacology but that's a novel argument to me. Yes, I'm sure the manufacturing process is complex. And yes, any variation in potency, particularly for an anticoagulant, especially one whose biological effect cannot be monitored readily in most hospitals, could be a critical patient safety issue. The issue of potency variation in generic drugs has been raised before, for drugs such as thyroxine. A generic drug does not have to prove efficacy and safety to get approved, only bioequivalence. For some drugs the FDA's bioequivalence standards permit variation in potency on the order of 25% form the brand name drug. This could be highly significant for drugs with a narrow therapeutic window, particularly those like Lovenox where the biologic effect cannot be easily monitored.

I don't know if that's the concern here, but it's plausible. As a member of SHM, I hope they explain.

Dr RW,Thanks for bringing this story up. As a medical student (with a previous career in the financing/business development of biotech) about to venture into my residency training, I find it disappointing that these MD's put their name to this when they have such an obvious conflict which they fail to disclose in their arguments.

I am also familiar with the Momenta technological approach to characterizing complex mixtures such as lovenox, copaxone and other complex biologic mixtures. I can say with some level of confidence that they truly are taking a unique approach to the analysis and that, rather than just throwing mountains of data at the FDA, their technology allows them a multi-dimensional understanding of "whats in the vial" (their approach is pretty well explained in their materials). As a result, they likely know more about lovenox and copaxone (their other generic candidate) than the innovators do.

Unfortunately, the challenge is that, with the innovators, complete characterization is unnecessary when first developing their products. They only need to know the active ingredient and develop a consistent and safe/monitorable manufacturing process and show through trials that what comes out the end of the pipe is indeed consistently safe and effective. For Momenta/Sandoz, the challenge is that they have to convince everyone that they have actually adequately characterized the innovator product to act as a baseline comparator and then they have to develop their own manufacturing process that produces a product that is then also characterized fully and shown to be highly similar or within the range for "bioequivalence".

For those innovators that do not understand the Mom/Sandoz approach, they do not see how you can manufacture this complex mixture in a different way (since Mom/Sandoz do not know the exact recipe that Aventis uses) and still come up with an adequately similar product. There indeed should be many questions answered around the impact any differences in the mixtures may have in clinical practice, thus the FDA's earlier request for more data on immunogenicity.

Unlike the generics in the "small molecule" world where basically there is an easily identified and highly purified active ingredient and a known delivery media, this is a much larger task, both for Momenta/Sandoz and for the FDA. I think that they will ultimately gain approval, but the FDA will be very careful in opening up what could be a huge game-changing field.

For those innovators that do not understand the Mom/Sandoz approach, they do not see how you can manufacture this complex mixture in a different way (since Mom/Sandoz do not know the exact recipe that Aventis uses) and still come up with an adequately similar product and there indeed should be many questions answered around the impact any differences in the mixtures may have in clinical practice, thus the FDA's earlier request for more data on immunogenicity. Unlike the generics in the "small molecule" world where basically there is an easily identified active ingredient and a known delivery media, this is a much larger task, both for Momenta/Sandoz and for the FDA. I think that they will ultimately gain approval, but the FDA will be very careful in opening up what could be a huge game-changing field.